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WO2011076086A1 - Composés intermédiaires du tamiflu, procédés de préparation associés et utilisations associées - Google Patents

Composés intermédiaires du tamiflu, procédés de préparation associés et utilisations associées Download PDF

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Publication number
WO2011076086A1
WO2011076086A1 PCT/CN2010/079936 CN2010079936W WO2011076086A1 WO 2011076086 A1 WO2011076086 A1 WO 2011076086A1 CN 2010079936 W CN2010079936 W CN 2010079936W WO 2011076086 A1 WO2011076086 A1 WO 2011076086A1
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reaction
compound
group
solvent
carbons
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English (en)
Chinese (zh)
Inventor
马大为
朱少林
俞寿云
王优
周强辉
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Shanghai Institute of Organic Chemistry of CAS
Lianhe Chemical Technology Co Ltd
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Shanghai Institute of Organic Chemistry of CAS
Lianhe Chemical Technology Co Ltd
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Priority to US14/123,870 priority Critical patent/US9040738B2/en
Publication of WO2011076086A1 publication Critical patent/WO2011076086A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/02—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols
    • C07C319/12—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols by reactions not involving the formation of mercapto groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C229/66—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring the carbon skeleton being further substituted by doubly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/30—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
    • C07C233/31—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/18—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by doubly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/61—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the method of the invention relates to an intermediate compound of the anti-influenza drug Tamiflu, a synthesis method and use thereof. Background technique
  • Tamiflu ® the scientific name Oseltamivir, Chinese name Osmivir (trade name Tamiflu), is an ethyl ester prodrug of GS-4071 that blocks the cleavage of sialic acid residues on the surface of virus-infected cells by influenza virus NA. Thereby inhibiting the release of new virions from the host cell.
  • Oseltamivir has a high oral activity and is metabolized by in vivo hepatic esterase to produce active GS-4071, which produces an inhibitory effect against influenza virus NA.
  • Oseltamivir was developed and produced by Roche and marketed in Switzerland in 1999. Its tablets are the first orally convenient influenza virus NA inhibitors for the treatment of influenza A and B, and can reduce otitis media in patients aged 1-12 years. .
  • Tamiflu's phosphate (Oseltamivir phosphate, GS-4101/002) was approved by the US FDA for use in people over the age of 13 to prevent influenza A and B. At the same time, Tamiflu is well tolerated and there are no reports of serious side effects.
  • Hayashi proposed a synthetic route in 2009 with a total yield of 57% (Angew. Chem. Int. Ed. 2009, 48, 1304).
  • the avian flu caused by the H5N1 virus in recent years has made Tamiflu more and more demanding.
  • Multi-substituted chiral tetrahydropyrrolamine intermediates are widely present in a variety of drugs or active molecules, such as:
  • Asymmetric catalysis provides chemists with new powerful tools for efficiently synthesizing complex molecules.
  • organocatalysis has flourished and quickly became a new field of asymmetric catalysis. Chem. Int. Ed. 2001, 40, 3726).
  • Organic catalysis is a bridge between metal organic catalysis and enzymatic catalysis as well as synthetic chemistry and bioorganic chemistry. Thanks to the wide range of catalyst sources, easy to prepare, cheap; easy to operate, generally do not need anhydrous and oxygen-free; avoid the advantages of toxic metal residues, organic catalysis has caused great interest in the chemical industry and industry, authoritative magazine Continuous review has become a hot topic.
  • the asymmetrically catalyzed enantioselective Michael addition reaction has long been considered to be the most powerful and reliable method for forming CC bonds and C-hetero bonds.
  • a large number of examples have been applied in total synthesis. Because of this, in recent years, A large number of organically catalyzed Michael reactions have been reported, including various nucleophiles and Michael Receptor Synthesis 2007, 14, 2065-2092).
  • Michael reactions in Domino reactions or One-pot reactions to efficiently construct complex molecules in multi-chiral centers has become a hot research area.
  • the object of the present invention is to provide a chiral amine-based compound which can be used as a key intermediate of Tamiflu, a chiral tetrahydropyrrolamine pharmaceutical intermediate;
  • the object of the present invention is also to provide a method for synthesizing the above compound, which is easy to obtain and easy to apply to industrial production.
  • Another object of the present invention is to provide a use of the above compounds, that is, a more convenient and economical synthesis of a Tamiflu drug, and a synthesis of a multi-substituted chiral tetrahydropyrrolamine pharmaceutical intermediate.
  • Another object of the invention is to provide two intermediate compounds for the preparation of Tamiflu.
  • the chiral amine-based compound provided by the present invention has the following
  • alkyl group of 1 to 10 carbons an alkoxy group of 1 to 10 carbons (preferably 3-pentyloxy group), an alkenyl group of 2 to 6 carbons (preferably an isobutenyl group), and 1 to 4 carbons substituted.
  • an alkyl group of 1 to 4 carbons an alkoxy group of 1 to 4 carbons, an alkyl group of 1 to 4 carbons substituted by F, a phenyl group, an electron withdrawing group or an electron donating group, monosubstituted, disubstituted or Trisubstituted phenyl;
  • the F is an amino group, a substituted amine group, a hydroxyl group, a substituted hydroxyl group (preferably a benzyloxy group), an alkylcarbonyloxy group of 2 to 10 carbons or an alkenyl group of 2 to 6 carbons; the substituted amine Substituents on the group are tert-butoxycarbonyl, benzyloxycarbonyl, benzyl
  • acetyl trifluoromethylcarbonyl or phthaloyl ( );
  • a substituted benzyl group an acetyl group, methoxymethyl, t-butyl dimethyl silicon, trimethylsilyl, triethylsilyl, diphenyl-t-butyl substituted on the hydroxy a silicon group or a 2-tetrahydropyranyl group;
  • the electron withdrawing group is preferably a halogen, a nitrile group or a nitro group, such as a halogen? , Cl, Br or I
  • the electron donating group is preferably an alkyl group of 1 to 4 carbons, an alkoxy group of 1 to 4 carbons, an amine group or a hydroxyl group.
  • R 2 and R 3 are independently a protecting group for nitrogen or hydrogen, and the protecting group for said nitrogen is t-butoxycarbonyl, benzyloxycarbonyl,
  • chiral amine-based compound of the present invention is recommended to have any of the following structural formulas or enantiomers thereof:
  • Boc tert-butoxycarbonyl
  • Bn benzyl
  • (; acetyl
  • Phth phthaloyl
  • Cbz stands for benzyl
  • reaction formula for synthesizing the chiral amine-based compound R 3 or R 2 of the present invention is substantially the same as above, except that the catalyst is the corresponding enantiomer.
  • R 2 and R 3 are as defined above.
  • the method of synthesizing the above chiral amine-based compound of the present invention can be further described as:
  • the above aldehyde and nitroene are reacted in a certain solvent for 10 min to 48 h in the presence of a catalyst and an additive.
  • the reaction is preferably carried out at -20 ° C to 30 ° C, and the additive is an organic acid or a weak base salt.
  • the catalyst has the following structural formula:
  • Ar , R 3 is as defined above; such as di-tert-butylmethylsilyl, trimethylsilyl, H or a combination thereof;
  • the additive is recommended to be acetic acid, sodium acetate, chloroacetic acid, bromoacetic acid in an organic or weak base salt One or more of sodium acetate, benzoic acid and substituted benzoic acid;
  • the solvent is recommended water, dichloromethane, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, methanol, ethanol, toluene, hydrazine One or more of hydrazine-dimethylformamide, ethylene glycol dimethyl ether and dimethyl sulfoxide;
  • the molar ratio of the aldehyde, nitrone, catalyst and additive is recommended (1.0-4.0): (1.0-2.0): (0.01-0.20): (0-0.50)
  • Base compound also relates to a method for preparing Duffy comprising the following steps:
  • R 5 represents an unsubstituted, monosubstituted or polysubstituted 6 to 12 carbon aryl group or a 1 to 6 carbon alkyl group, and the aryl substituent is a halogen, a nitro group, an alkyl group of 1 to 3 carbons. Or an alkoxy group of 1 to 3 carbons, most preferably a p-tolyl group.
  • the method and conditions of the reduction reaction may be conventional methods and conditions for such reactions in the art, and the present invention particularly preferably the following methods and conditions: in a solvent, in zinc powder and trimethyl chloride Under the action of silane, acetic acid or hydrochloric acid, the compound hydrazine is subjected to a reduction reaction of a nitro group to obtain a compound I.
  • the solvent is preferably an alcohol solvent such as ethanol and/or methanol, and ethanol is preferred.
  • the volumetric mass of the solvent and the compound II is preferably from 10 to 40 ml/g.
  • the amount of the zinc powder is preferably 10 to 30 times, preferably 20 times the molar amount of the compound II.
  • the amount of the trimethylchlorosilane to be used is preferably 10 to 20 times, preferably 15 times the molar amount of the compound.
  • the volumetric mass of acetic acid or hydrochloric acid and compound II is preferably from 10 to 40 ml/g, preferably 25 ml/g.
  • Acetic acid or hydrochloric acid is preferably present in the form of an aqueous solution.
  • the concentration of the aqueous hydrochloric acid solution is preferably 0.1 M to 12 M, and the concentration of the aqueous acetic acid solution is preferably 1% to 100%.
  • the reaction time is preferably such that the reaction is completed, usually from 1 to 3 hours.
  • the temperature of the reaction is preferably 40 to 80 ° C, preferably 70 ° C.
  • the method and conditions for the reaction for removing R 5 S may be conventional methods and conditions for such reactions in the art, and the following methods and conditions are particularly preferred in the present invention: in a solvent, in a base and Under the action of ammonia gas, the compound I can be subjected to a reaction of removing R 5 SH.
  • the solvent is preferably an alcohol solvent such as ethanol and/or methanol, and ethanol is preferred.
  • the volumetric mass of the solvent and the compound hydrazine is preferably from 10 to 40 ml/g.
  • the base is preferably potassium carbonate.
  • the amount of the base is preferably from 5 to 15 times the molar amount of the compound hydrazine.
  • the amount of the ammonia gas is preferably from 10 to 25 times the molar amount of the compound hydrazine.
  • the reaction time is preferably such that the reaction is complete, typically 5-20 minutes.
  • the temperature of the reaction is preferably -10 to 30 ° C, preferably 0 ° C.
  • the compound ⁇ can be obtained by the following method: the compound m is subjected to the addition reaction as shown below;
  • R 5 is defined as described above.
  • the method and conditions of the addition reaction may be the conventional methods and conditions for such reactions in the art of such a reaction, and the following methods and conditions are particularly preferred in the present invention: in the solvent, the compound m and R 5 SH
  • the solvent is preferably an alcohol solvent such as ethanol and/or methanol, preferably ethanol.
  • the volume of the solvent and the compound III is preferably 2 to 20 ml/g.
  • the amount of R 5 SH used is preferably from 2 to 10 times the molar amount of the compound III.
  • the reaction time is preferably such that the reaction is complete, usually from 1 to 3 days.
  • the temperature of the reaction is preferably -20 to 30 ° C, preferably -15 ° C.
  • the compound hydrazine can be obtained by the following method:
  • the compound IV and ethyl 2-diethoxy oxyphosphoric acid acrylate are reacted as follows;
  • the method and conditions of the reaction may be the conventional methods and conditions for such a reaction, and the following methods and conditions are particularly preferred in the present invention: in the solvent, under the action of a base, the compound IV and 2-diethoxy
  • the reaction of ethyl oxyphosphoric acid ethyl acrylate can be carried out.
  • the solvent is preferably one or more of dichloromethane, chloroform, toluene, ethanol and methanol, preferably dichloromethane and/or ethanol.
  • the volumetric mass of the solvent and the compound IV is preferably from 2 to 20 ml/g.
  • the base is preferably an inorganic carbonic acid base or an organic base, and the organic base may be DBU or the like.
  • the base is preferably cesium carbonate.
  • the base is preferably used in an amount of from 2 to 10 times, preferably 4 times, the molar amount of the compound IV.
  • the reaction time is preferably such that the reaction is completed, usually from 1 to 5 hours.
  • the temperature of the reaction is preferably -10 to 30 ° C, excellent Choose 30 °C.
  • the present invention also relates to a process for preparing an intermediate compound of lanthanum, which comprises the steps of: de-esterifying a compound ⁇ ' and eliminating a hydroxyl group;
  • X is an amino protecting group commonly used in the art, such as tert-butoxycarbonyl (Boc);
  • the methods and conditions for the deesterification and the elimination reaction of the hydroxyl group can be the conventional methods and conditions for such reactions in the art, and the following methods and conditions are particularly preferred in the present invention: in a solvent, under the protection of an inert gas, Under the action of an inorganic salt, the compound ⁇ ' can be subjected to deesterification and elimination of a hydroxyl group.
  • the solvent is preferably one or more of dimethylformamide, xylene and dimethyl sulfoxide, preferably dimethyl sulfoxide.
  • the volume of the solvent and the compound ⁇ ' is preferably from 2 to 100 ml/g.
  • the inorganic salt is preferably sodium chloride
  • the inorganic weak base is preferably used in an amount of from 0.1 to 5 times the molar amount of the compound.
  • the inert gas may be argon or nitrogen.
  • the temperature of the reaction is preferably from 100 to 250 ° C, more preferably from 150 to 180 ° C.
  • the reaction time is preferably such that the reaction is completed, usually from 2 to 10 hours.
  • the compound ⁇ ' can be obtained by the following method: by reacting the compound hydrazine with an upper amino protecting group;
  • X is an amino protecting group commonly used in the art, such as tert-butoxycarbonyl (Boc;).
  • the method and conditions for the reaction of the above-mentioned upper amino protecting group can be the conventional methods and conditions for such a reaction in the art, and the following methods and conditions are particularly preferred in the present invention:
  • X is Boc
  • the compound is ⁇ in the solvent.
  • the reaction with the tert-butoxycarbonyl protecting group of the upper amino group may be carried out with di-tert-butyl dicarbonate (Boc 2 0).
  • the solvent is preferably one or more of dichloromethane, tetrahydrofuran and acetonitrile, preferably acetonitrile.
  • Solvent and compound ⁇ volume The better amount is 2 ⁇ 100ml/g.
  • the di-tert-butyl dicarbonate is preferably used in an amount of from 1 to 5 times, more preferably from 1.0 to 1.5 times, the molar amount of the compound.
  • the temperature of the reaction is preferably -20 to 50 ° C, more preferably 0 to 25 ° C.
  • the reaction time is preferably such that the reaction is completed, usually from 0.5 to 3 hours.
  • the compound hydrazine can be obtained by the following method: the compound IV' is subjected to a reduction reaction of a nitro group;
  • the method and conditions for the reduction reaction of the nitro group may be the conventional methods and conditions for such a reaction in the art, and the present invention particularly preferably has the following methods and conditions: in the solvent, under the action of the metal Zn and acetic acid,
  • the compound IV' can be subjected to a reduction reaction of a nitro group.
  • the solvent is preferably methanol and/or ethanol, preferably ethanol.
  • the volumetric mass of the solvent and the compound IV' is preferably from 2 to 100 ml/g.
  • the amount of the metal Zn is preferably from 1 to 5 times, more preferably from 1.2 to 2 times the molar amount of the compound IV'.
  • the amount of the acetic acid to be used is preferably from 1 to 5 times, more preferably from 1 to 2 times, the mole of the compound IV'.
  • the temperature of the reaction is preferably from 0 to 60 ° C, more preferably from 0 to 25 ° C.
  • the reaction time is preferably such that the reaction is completed, usually from 0.5 to 6 hours.
  • the compound IV' can be produced by any of the following methods:
  • the compound V' may be subjected to a base-catalyzed isomerization reaction as shown below;
  • the method and conditions for the base-catalyzed isomerization reaction may be conventional methods and conditions for such reactions in the art, and the present invention particularly preferably has the following methods and conditions: in the solvent, in the inorganic weak
  • the compound V' may be subjected to an isomerization reaction by the action of a base.
  • the solvent is preferably one or more of dichloromethane, tetrahydrofuran and acetonitrile, preferably acetonitrile.
  • the volumetric mass of the solvent and the compound V' is preferably from 2 to 100 ml/g.
  • the inorganic weak base is preferably one or more of cesium carbonate, sodium carbonate, potassium phosphate and potassium carbonate, preferably potassium carbonate.
  • the amount of the inorganic weak base is preferably 0.1 to 5 times, more preferably 0.1 to 2 times, the compound V'.
  • the temperature of the reaction is preferably from -20 to 60 ° C, more preferably from 0 to 25 ° C.
  • the reaction time is preferably such that the reaction is completed, usually from 1 to 48 hours.
  • the method and conditions of the reaction may be conventional methods and conditions for such reactions in the art, and the present invention particularly preferably has the following methods and conditions: in a solvent, under the action of an inorganic weak base, Compound IV and ethyl 2-ethoxycarbonylacrylate can be subjected to intermolecular addition and intramolecular aldol reaction.
  • the solvent is preferably one or more of dichloromethane, tetrahydrofuran and acetonitrile, preferably acetonitrile.
  • the inorganic weak base is preferably one or more of cesium carbonate, sodium carbonate, potassium phosphate and potassium carbonate, preferably potassium carbonate.
  • the amount of the inorganic weak base is preferably from 0.1 to 5 times, more preferably from 0.1 to 2 times, based on the compound IV.
  • the molar ratio of the compound IV and ethyl 2-ethoxycarbonylacrylate is preferably from 0.1 to 1, more preferably from 0.3 to 1.
  • the temperature of the reaction is preferably -20 to 50 ° C, more preferably 0 to 25 ° C.
  • the reaction time is preferably such that the reaction is completed, usually from 1 to 10 hours.
  • the compound V' can be obtained by the following method: under the base catalysis, the compound IV and the ethyl 2-ethoxycarbonyl acrylate can be subjected to intermolecular addition and intramolecular aldol reaction;
  • preferred conditions are: a. 2-Ethoxyethoxyphosphoric acid ethyl acrylate, cesium carbonate, 0 ° C for 1 hour, ethanol, room temperature; b. p-methyl thiophenol; c. zinc powder, Trimethylchlorosilane, ethanol; d. ammonia, potassium carbonate, ethanol, room temperature.
  • preferred conditions are: a. potassium carbonate, acetonitrile, 0 ° C, 3 hours, then room temperature, 6 hours; b. potassium carbonate, acetonitrile, room temperature, 24 hours; c. zinc powder, acetic acid, ethanol, 70 ° C; d.
  • X Boc, (Boc) 2 0, acetonitrile, room temperature; e. lithium chloride, dimethyl sulfoxide, 190 ° C; f. TFA, dichloromethane.
  • the invention also relates to the preparation of intermediate compounds III, II, ⁇ ', ⁇ , IV' or V' of Tamiflu :
  • X is an amino protecting group commonly used in the art, such as tert-butoxycarbonyl (Boc;).
  • R 5 represents an unsubstituted, monosubstituted or polysubstituted 6 to 12 carbon aryl group, or a 1 to 6 carbon alkyl group, and the aryl substituent is a halogen, a nitro group, an alkyl group of 1 to 3 carbons or 1 to 3 carbon alkoxy groups.
  • the chiral amine-based compounds of the present invention can also synthesize a class of chiral tetrahydropyrrolamine pharmaceutical intermediates which are polysubstituted chiral tetrahydropyrroles and are preferably disubstituted chiral tetrahydropyrroles.
  • the present invention also relates to a process for the preparation of a chiral tetrahydropyrrolamine pharmaceutical intermediate of the formula VI or VI', which comprises the steps of: reducing the nitro group by reducing the compound VII or VII' and reducing the ammonia Chemical reaction, you can;
  • the preparation method is preferably any one of the following methods:
  • the compound VII or VII' is subjected to a reduction reaction of a nitro group and a reductive amination reaction under the action of a catalyst and hydrogen; 2.
  • the reduction reaction of the nitro group is first carried out by the compound ⁇ or ⁇ ', and then the reductive amination reaction is carried out.
  • the method and conditions for the reduction reaction and the reductive amination reaction of the nitro group may be the conventional methods and conditions for the two types of reactions in the art, and the following methods and conditions are particularly preferred in the present invention:
  • the polar solvent is preferably an alcohol solvent such as methanol and/or ethanol, and most preferably methanol.
  • the volume of the solvent and the compound VII or VII' is preferably from 50 to 200 ml/g.
  • the catalyst is preferably Pd/C, Pd(OH) 2 /C Pt0 2 or Ranny-Ni.
  • the weight of the compound VII or VII' and the catalyst is preferably from 1:0.001 to 0.2.
  • the pressure of hydrogen gas is preferably from 1 x 10 5 Pa to 100 x 10 5 Pa.
  • the time taken by the method is preferably performed to detect that the two reactions are complete.
  • the temperature of both reactions is preferably from 0 ° C to 100 ° C, preferably 20 ° C.
  • the reduction reaction of the nitro group is preferably carried out by reducing the nitro group of the compound VII or VII' under the action of Zn/HOAc, Fe powder or Ranny-Ni/H 2 in a solvent. reaction.
  • the usage and amount of the Zn/HOAc, Fe powder, or R a tmy-Ni/H 2 can be the conventional usage and dosage of such reactions in the field.
  • the Zn/HOAc or Fe powder is used as the reducing agent
  • the Zn (e.g., zinc powder) or iron powder is preferably used in an amount of 10 to 30 times, preferably 25 times, the molar amount of the compound VII or VII'.
  • the solvent is preferably acetic acid or a mixed solution of acetic acid and water (preferably 1:0.5 ⁇ 2), and the volume of the solvent and the compound VII or VII' is preferably 20 to 100 ml/g.
  • the time during which the reduction reaction is carried out is preferably carried out until the reaction is completed, usually from 1 to 24 hours, and the reaction temperature is preferably from 0 ° C to 100 ° C, preferably 20 ° C.
  • the weight of the compound VII or VII' and the catalyst Ranny-Ni is preferably 1:0.001-0.2.
  • the pressure of hydrogen is preferably lx l0 5 Pa ⁇ 100 x 10 5 Pa
  • the optimum solvent is an alcohol solvent such as ethanol and/or methanol
  • the reduction reaction is preferably carried out to detect the completion of the reaction, generally 1-
  • the reaction temperature is preferably from 0 ° C to 100 ° C, preferably 20 ° C, for 24 hours.
  • the reductive amination reaction is preferably carried out by a method in which a substance obtained by a reduction reaction of a nitro group is subjected to a reductive amination reaction under a action of a reducing agent.
  • the solvent is preferably one or more of dichloromethane, tetrahydrofuran and 1,2-dichloromethane.
  • the volume of the solvent and the compound VII or VII' is preferably from 20 to 100 ml/g.
  • the reducing agent is preferably sodium borohydride, sodium cyanoborohydride, sodium borohydride borohydride, borofluorene/pyridine, sodium borohydride/magnesium perchlorate, zinc borohydride/zinc chloride, or triacetoxyborohydride. sodium.
  • the reducing agent is preferably used in an amount of from 1 to 4 times the molar amount of the compound VII or VII'.
  • the reaction time is preferably such that the reaction is completed, usually from 0.5 to 2 hours.
  • the temperature of the reaction is preferably from 0 to 30 °C.
  • Such polysubstituted chiral tetrahydropyrroleamine intermediates can further synthesize a variety of drugs or active molecules.
  • the present invention provides a method for synthesizing a chiral amine-based compound, and the present invention provides a method for synthesizing Teffi from the intermediate, which is easy to obtain raw materials, simple in operation, short in route, and suitable for industrial production, and provides This intermediate synthesizes a class of polysubstituted chiral tetrahydropyrrolamine pharmaceutical intermediates.

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Abstract

La présente invention concerne des composés aminés chiraux, des procédés de préparation associés et les utilisations associées. Le Tamiflu peut être obtenu à partir desdits composés. Une tétrahydropyrrolyl-amine chirale multisubstituée qui peut être utilisée à titre de composé intermédiaire du médicament peut également être produite par lesdits composés.
PCT/CN2010/079936 2009-12-23 2010-12-17 Composés intermédiaires du tamiflu, procédés de préparation associés et utilisations associées Ceased WO2011076086A1 (fr)

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CN114634471A (zh) * 2022-04-14 2022-06-17 河南师范大学 一种合成γ-羟基-γ-全氟甲基环外双键丁内酯类化合物的方法

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CN102643256B (zh) 2011-02-18 2014-12-24 上海璎黎科技有限公司 一种芳基糖苷类化合物及其制备方法和应用
JP5784336B2 (ja) * 2011-03-08 2015-09-24 公益財団法人微生物化学研究会 化合物、及びその製造方法、並びにリン酸オセルタミビルの製造方法
CN102180821A (zh) * 2011-03-10 2011-09-14 杭州师范大学 一种达菲中间体及其合成方法
CN111018901B (zh) * 2013-09-09 2021-09-03 中国科学院上海有机化学研究所 扎那米韦和拉那米韦的中间体及其合成方法
CN107121506B (zh) * 2017-04-13 2019-06-07 杭州华东医药集团新药研究院有限公司 奥泽沙星杂质及其用途
CN107304171A (zh) * 2017-05-05 2017-10-31 杭州师范大学 一种奥司他韦的合成方法
CN111763157B (zh) * 2020-04-26 2021-10-26 中山大学 一种手性氨基化合物及其制备方法和应用、及由其制备依度沙班中间体的制备方法
CN116396141B (zh) * 2023-04-17 2025-05-30 中国科学技术大学 一种溴氯化物或溴叠氮化物的制备方法

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WO2009078813A1 (fr) * 2007-12-19 2009-06-25 Nanyang Technological University Procédé de formation d'oseltamivir et de ses dérivés et applications correspondantes
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CN114634471B (zh) * 2022-04-14 2023-05-19 河南师范大学 一种合成γ-羟基-γ-全氟甲基环外双键丁内酯类化合物的方法

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